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WO2008119772A1 - Dérivés d'amide utilisés en tant qu'inhibiteurs d'aspartyl-protéases - Google Patents

Dérivés d'amide utilisés en tant qu'inhibiteurs d'aspartyl-protéases Download PDF

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WO2008119772A1
WO2008119772A1 PCT/EP2008/053765 EP2008053765W WO2008119772A1 WO 2008119772 A1 WO2008119772 A1 WO 2008119772A1 EP 2008053765 W EP2008053765 W EP 2008053765W WO 2008119772 A1 WO2008119772 A1 WO 2008119772A1
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alkyl
methyl
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phenyl
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Ingemar KVARNSTRÖM
Fredrik WÅNGSELL
Åsa ROSENQUIST
Bertil Samuelsson
Christer Sahlberg
Christian Sund
Oscar Belda
Vladimir Ivanov
Lourdes Oden
Rolf NORÉN
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Medivir AB
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Medivir AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/07—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • This invention relates to novel compounds having inhibitory activity on aspartyl proteases such as rennin and ⁇ -secretase ( ⁇ -site amyloid precursor protein-cleaving enzyme, BACE). It further concerns pharmaceutical compositions comprising these compounds as active ingredients as well as processes for preparing these compounds and compositions and their in the preparation of a medicament or their use in therapy.
  • aspartyl proteases such as rennin and ⁇ -secretase ( ⁇ -site amyloid precursor protein-cleaving enzyme, BACE).
  • a number of aspartic proteases are known to date, including pepsin A and C, Renin, BACE, BACE2, Napsin and Cathepsin D, which have been implicated in pathological conditions.
  • aspartyl protease BACE causes the production of the protein ⁇ amyloid (A ⁇ ) in the brain, which is characteristic of Alzheimer's disease (AD).
  • AD is a progressive neurogdegenerative disease of the brain characterized by gradual loss of cognitive function related to memory, reasoning, orientation and judgement and eventually death.
  • Pathological features of AD is accumulation of abnormal aggregated protein breakdown products, ⁇ -amyloid plaque and neurofibrillary tangles, in the brain.
  • Plaque relatively specific for AD is primary a result from extracellular accumulation of aggregated A ⁇ .
  • Fibrillary tangles consists mainly of hyperphosphorylated tau protein and are also found in other neurodegenerative disorders. It is believed that A ⁇ is the fundamental causative agent of neuronal cell loss and dysfunction which is associated with cognitive and behavioural decline.
  • a ⁇ is a peptide comprised of 40-42 amino acid residues, which is formed by proteolytic cleavage of the large transmembrane amyloid precursor protein (APP).
  • APP large transmembrane amyloid precursor protein
  • APP is processed along two pathways, the major ⁇ - and the minor ⁇ -secretase pathway.
  • the ⁇ -secretase pathway results in non-pathogenic products known as soluble APP, whereas the ⁇ - secretase pathway produces pathogenic A ⁇ peptides by cleavage by ⁇ -secretase at the position corresponding to the N-terminus of A ⁇ , followed by cleavage by ⁇ -secretase at the C-terminus.
  • a ⁇ amyloid cascade hypothesis, supported by genetic and pathological evidence, claims that the formation of A ⁇ plays an early and vital role in all cases of AD.
  • a ⁇ forms aggregates that are thought to initiate a pathogenic cascade that leads to neuronal loss and dementia.
  • BACE was identified a few years ago as a type 1 glycosylated transmembrane homodimer with two aspartic acids at the active catalytic site.
  • BACE and BACE-2 (64 % amino acid sequence similarity to BACE) constitute a novel class of aspartic proteases closely related to the pepsin family.
  • the function of BACE-2 is relatively unknown and several studies indicate that this enzyme is not involved in the A ⁇ generation.
  • BACE knockout homozygote mice show complete absence of producing A ⁇ and the animals appear to develop normally and have no discernable abnormalities. Tissue cultures and animal studies indicated that ⁇ -secretase is expressed in all tissues but at highest levels in the neurons in the brain. Therefore, in vivo inhibition of BACE is likely to reduce the production of A ⁇ and is considered to be an attractive therapeutic target for the treatment and prevention of AD.
  • Renin The protease Renin is involved in the renin-angiotensin system (RAS) which is critical for the control of blood pressure and salt balance in mammals. Renin has a high substrate specificity, its only known substrate is angiotensinogen. Renin cleaves the N terminus of circulating angiotensinogento angiotensin I (Ang I) which thereafter is further processed to the active peptide hormone angiotensin II (Ang II) by the less specific angiotensin-converting enzyme (ACE). Ang II increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating the sodium- ion-retaining hormone aldosterone. Ang II is known to work on at least two receptor subtypes called ATI and AT2. ATI seems to transmit most of the known functions of Ang II, while the role of AT2 is still unknown.
  • RAS renin-angiotensin system
  • Modulation of the RAS represents a major advance in the treatment of cardiovascular diseases. Inhibition of the enzymatic activity of renin leads to a reduction in the formation of Ang I, and as a consequence, a smaller amount of Ang II is produced. The reduced concentration of that active peptide hormone is a direct cause of the hypotensive effect of renin inhibitors.
  • ACE inhibitors and ATI blockers have been accepted to treat hypertension and ACE inhibitors are used for renal protection in the prevention of congestive heart failure and myocardial infarction.
  • the rationale to develop renin inhibitors is the specificity of renin. Renin inhibitors are expected to demonstrate a different pharmaceutical profile than ACE inhibitors and ATI blockers with regard to efficacy in blocking the RAS and in safety aspects.
  • renin inhibitors With good oral bioavailability and long duration of action are required.
  • the present invention concerns inhibitors of renin which exhibit beneficial potency, selectivity and/or pharmacokinetic properties. Brief description of the Invention
  • aspartyl protease inhibitors which can be represented by the formula (I):
  • R 2 is H or Ci-C 6 alkyl
  • R 3 is Ci-C 6 alkyl, Ci-C 6 alkoxyCi-C 3 alkyl, Ci-C 3 alkanediylaryl, Ci-C 3 alkanediylheterocyclyl;
  • R 4 is Ci-C ⁇ alkyl and R 4 is H; or R 4 and R 4 together with the carbon atom to which they are attached define C 3 -C6Cycloalkyl;
  • R 7 is Ci-C 6 alkyl, Ci-C 6 alkoxyCi-C 3 alkyl, hydroxyCi-C 3 alkyl, Ci-C 3 alkanediylNRaRb, aryl, heterocyclyl, C 3 -Cecycloalkyl, Ci-C 3 alkanediylC 3 -C 6 Cycloalkyl, Ci-C 3 alkanediylaryl, Ci- C 3 alkanediylheterocyclyl, Ci-C 3 alkanediyl-0-Co-C 3 alkanediyl aryl or Ci-C 3 alkanediyl-0-Co- C 3 alkanediyl heterocyclyl; wherein the Ci-C 3 alkanediylmoiety is optionally substituted with Ci-C ⁇ alkyl; R 8 is H, Ci-Cealkyl; or
  • R 7 and R 8 together with the N atom to which they are attached define a heterocyclyl group
  • R 9 is H, Ci-Cealkyl, Ci-C 6 alkoxy, Ci-C 6 alkoxyCi-C 3 alkyl or Ci-C 6 alkoxyCi-C 6 alkoxyC 0 - C 3 alkyl;
  • E is -CH(Rc)-CH(Rc)-, -NRd-CH(Rd)-, -CH(Rd)-NRd-, NRd-NRd-, -CH(Rd)-O-, -0-CH(Rd)-, -CH(Rc)-, -NRd-, or -0-;
  • Q is aryl or heterocyclyl;
  • W is H, Ci-C ⁇ alkyl, C 3 -Cecycloalkyl, aryl or heterocyclyl;
  • X' is H, F, OH, or NRaRb;
  • X" is H or when X' is F, X" can also be F;
  • Y is H, Ci-Cealkyl, Ci-C 6 alkoxy, Ci-C 6 alkoxyCi-C 3 alkyl, Ci-C 6 alkoxy-Ci-C 6 alkoxy, C 0 - C 3 alkankediylaryl, Co-C 3 alkankediylC 3 -C 6 Cycloalkyl or Co-C 3 alkankediylheterocyclyl;
  • ring A is a saturated, partially unsaturated or aromatic ring;
  • m is O or 1, whereby ring A defines a cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or a phenyl ring;
  • n is 0, 1, 2 or 3;
  • p is 0 or 1 ;
  • q is 0, 1 or 2; thereby defining a bond, methylene or ethylene, or when q is 1,
  • Ra is H or Ci-C 6 alkyl
  • Rb is H or Ci-C ⁇ alkyl; or Ra and Rb together with the nitrogen to which they are attached define a heterocyclyl group;
  • Rc is H, Ci-Cyalkyl, Ci-C 6 alkoxy, Ci-C 6 alkoxyCi-C 3 alkyl, Ci-C 6 alkoxyCi-C 6 alkoxy, hydroxyCo-C 3 alkyl or C 0 -C 3 alkandiylNRaRb;
  • Rd is H, Ci-Cyalkyl, Ci-C 6 alkoxyCi-C 3 alkyl, Ci-C 6 alkoxyCi-C 6 alkoxyCi-C 3 alkyl, hydroxyCi-
  • Ci-C 3 alkandiylNRaRb where aryl is independently phenyl, naphthyl, or phenyl fused to Cs-C ⁇ cycloalkyl or C 5 -
  • C ⁇ cycloalkenyl aryl is phenyl, naphthyl or phenyl fused to Cs-C ⁇ cycloalkyl or Cs-C ⁇ cycloalkenyl; heterocyclyl is independently a 5 or 6 membered, saturated, partially unsaturated or heteroarylic ring containing 1 to 3 heteroatoms independently selected from S, O and N, the ring being optionally fused with a benzene ring; and wherein each occurrence of Ci-C ⁇ alkyl, C 2 -Cealkenyl, C 2 -Cealkynyl, C 3 -Cecycloalkyl, aryl and heterocyclyl above (including those in composite expressions such as alkoxy or alkanediylaryl) is optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from Ci-C 4 alkyl (optionally substituted with 1 or 2 substituents independently selected from Co-C 3 alkandiylaryl
  • Ci-C 4 alkoxyCi-C 6 alkoxyCo-C 3 alkyl Ci-C 4 alkoxyCi-C 6 alkoxyCo-C 3 alkyl, halo, haloCi-C 4 alkyl, polyhaloCi-C 4 alkyl, hydroxy, hydroxyCi-C4alkyl, amino, aminoCi-C4alkyl, carbamoyl, amido, cyano, azido, Ci-
  • C 4 alkylcarbonyl a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, (any of which cyclic amines being optionally substituted with Ci-C 4 alkyl or fluoro), Co-C 3 alkanediylC 3 -C 6 Cycloalkyl, Co-C 3 alkanediylaryl , Co-C 3 alkanediylheterocyclyl ,
  • the compounds of general formula (I) have several centres of chirality, conveniently the compounds display at least 75%, preferably at least 90%, such as in excess of 95%, enantiomeric purity at each of the chiral centres.
  • the chiral centre whereto the group R 2 is attached has the stereochemistry shown in the partial structure:
  • Z is O. According to other embodiments Z is NRa, wherein Ra is hydrogen or Ci-C 3 alkyl, preferably hydrogen or methyl.
  • the group Q is bonded either directly to Z, i.e. n is 0, or Q is bonded via a methylene, ethylene or propylene moiety, i.e. n is 1, 2 or 3 respectively.
  • Q is bonded to Z via an ethylene moiety, i.e. n is 2.
  • Q is bonded via a bond or a methylene moiety, i.e. n is 0 or 1 respectively.
  • Q is aryl or heterocyclyl, optionally substituted with one, two or three substituents independently selected from Ci-C4alkyl (optionally substituted with Co- Csalkandiylaryl , amino, carbamoyl, amido or Ci-C 4 alkoxyamido), C 2 -Cealkenyl, C 2 -Cealkynyl, C 3 -C 6 cycloalkyl, Ci-C 4 alkoxy, halo, haloCi-C 4 alkyl, polyhaloCi-C 4 alkyl, Ci-C 4 alkoxyCi- Csalkyl, Ci-C 4 alkoxyCi-C 6 alkoxyCo-C 3 alkyl, hydroxy, hydroxyCi-C 4 alkyl, cyano, azido, Ci- C 4 alkylcarbonyl, carbamoyl, amino, amido, a cyclic amine selected from pyrrolidinyl, piperidiny
  • Q is an optionally substituted mono or bicyclic aryl moiety such as phenyl or naphthyl.
  • Q is an optionally substituted mono- or bicyclic ring containing 1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, independently selected from nitrogen, oxygen and sulphur.
  • Representative monocyclic rings according to this embodiment include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like
  • representative bicyclic rings include quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl each of which is optionally substituted wherein each of the mono and bicyclic rings is optionally substituted.
  • Typical values for Q include 5 or 6 membered aryl or heterocyclyl, preferably phenyl or pyridyl, which is optionally substituted with one two or three substituents.
  • heterocyclyl groups for Q include pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, any of which may be substituted as defined above, such as with 1 or 2 Ci-C 4 alkyl (preferably methyl), Ci-C4alkoxy (preferably methoxy), Ci ⁇ alkoxyCi-C ⁇ alkoxyCo-Csalkyl, (preferably methoxypropoxy) groups or with one or two halogen atoms (preferably fluoro).
  • a further typical value for Q is optionally substituted naphthyl.
  • Optional substituents to Q are as defined above. Representative values include one or two substituents independently selected from Ci-C 4 alkyl, Cs-C ⁇ cycloalkyl, Ci-C 4 alkoxy, C 1 - Csalkoxy-Ci-C ⁇ alkoxyCo-Csalkyl, halo and haloCi-C 4 alkyl.
  • favoured values for the optional substituents to Q include cyclopropyl, methoxy- ethoxy, fluoro, optionally substituted phenyl and benzyl, more favoured substituents are chloro, methyl and methoxy-propoxy.
  • substituents to Q include Co-C 3 alkanediylaryl which aryl is optionally substituted, Co-C3alkanediylheterocyclyl and Co-C3alkanediylheteroaryl.
  • Typical heterocyclyl and heteroaryl include, but are not limited to, pyrrolyl, pyrrolinyl, pyrazolyl, imidazolyl, oxazolyl, pyrimidinyl, pyrazinyl, morpholinyl and especially furyl, thienyl, thiazolyl and pyridyl.
  • Q is a monosubstituted 6-membered aryl or heterocyclyl, wherein the substituent is preferably in the meta or para position.
  • Q is para substituted phenyl.
  • Q is meta substituted phenyl.
  • Preferred substituents according to this embodiment include chloro and fluoro.
  • Q is disubstituted phenyl with the substituents in the two meta positions or with one substituent in the meta position and the other in the para position.
  • Preferred substituents to Q according to this embodiment are independently chloro, fluoro, methoxypropoxy and methyl.
  • a typical embodiment for Q is phenyl, which is optionally substituted with one or two substituents independently selected from Ci-C 4 alkyl such as methyl, ethyl or isopropyl, cycloalkyl such as cyclopropyl, halo such as fluoro or chloro, and such as 2-methoxy-ethoxy or 3-methoxy-propxy.
  • Q include phenyl which is substituted with pyridyl, phenyl, substituted phenyl such as fluoro- or chloro -phenyl, cycloalkyl such as cyclopropyl or Ci-C ⁇ alkyl such as methyl, ethyl or isopropyl.
  • Q is mono- or di-substituted phenyl, wherein the substituents are in the meta position and/or in the para position.
  • Suitable configurations for Q include phenyl which is substituted in the meta position with Ci- C4alkoxyCi-C6alkoxy, and in the para position with Ci-C4alkyl, cyano or halo.
  • Q include phenyl which is substituted in the meta position with Ci-C4alkoxyCi-C6alkoxy, such as 3-methoxy-propoxy or 2-methoxy-ethoxy and in the para position with methyl, ethyl, cyclopropyl, fluoro, chloro or cyano.
  • Q include phenyl which is substituted in the meta position with Ci-C4alkoxyCi-C6alkoxy, such as 3-methoxypropoxy or 2-methoxy-ethoxy and/or in the para position with optionally substituted heteroaryl or optionally substituted phenyl.
  • Q include phenyl which is substituted in the meta position with 3-methoxy-propoxy and/or in the para position with pyridyl, thienyl or furyl or with optionally substituted phenyl, such as p-fluorophenyl.
  • a further configuration for the optional substituents to Q is benzyl which is substituted at the benzylic position.
  • Suitable substituents for the benzylic position includes for example amino, amido or alkoxyamido such as Ci-C4alkylamino or tert.butoxycarbonylamino.
  • R 5 is Ci-C 4 alkyl, Ci-C 4 alkylcarbonyl or Ci-C 4 alkyloxycarbonyl and R 5 is hydrogen, methyl or especially phenyl.
  • R 2 is Ci-C ⁇ alkyl such as methyl or ethyl, or preferably R 2 is hydrogen.
  • the chiral centre to which X' and X" are attached typically has the configuration shown in the partial structure:
  • X" X' X' and X" are as defined above, preferably X' is fluoro, or more preferably hydroxy.
  • X' and X" are both fluoro.
  • the chiral centre whereto the group R 3 is attached has the stereochemistry shown in the partial structure:
  • R 3 is d-C ⁇ alkyl, preferably sec.butyl or more preferably ethyl or isopropyl.
  • the invention includes compounds of general formula (I) wherein p is 0 or 1, i.e. compounds according to structures (Ia) and (Ib) respectively.
  • R 4 is hydrogen
  • the configuration corresponding typically to that of an L-amino acid.
  • R 4 is Ci-C ⁇ alkyl, such as sec.butyl or isopropyl.
  • R 4 is preferably hydrogen.
  • Preferred compounds of formula (I) are those having the stereochemistry indicated in formula (Ic):
  • ring A in general formula (I) is a six membered ring, i.e. m is 1.
  • Representative values for ring A according to these embodiments include cyclohexyl and phenyl, preferably phenyl.
  • ring A is a five membered ring, i.e. m is 0.
  • Preferred values for ring A according to these embodiments include cyclopentenyl and cyclopentyl, preferably cyclopentyl.
  • ring A is cyclopentyl
  • the stereochemistry is typically as indicated in the partial structures below:
  • the chiral centre to which R .6 is attached has typically the configuration as shown in the partial structure below:
  • R 7 is as recited above. Typical values for R 7 include Ci-C ⁇ alkyl, Ci-C 3 alkanediylaryl or Ci- Csalkanediylheterocyclyl, wherein each Ci-C ⁇ alkyl, cycloalkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from haloCi- C4alkyl, Ci-C4alkyl, Ci-C4alkoxy, hydroxy and cyano.
  • R 7 includes Ci-C 3 alkanediylaryl, wherein the C 1 - Csalkanediyl moiety is optionally substituted with R 7 , preferred values for R 7 include C 1 - C 4 alkyl, such as ethyl or preferably methyl.
  • R 7 favoured values for R 7 include benzyl, 1 -phenylethyl and 1-phenylpropyl, especially benzyl and 1 -phenylethyl, wherein the phenyl ring is optionally substituted.
  • the substituent(s) are in the para and/or ortho position of the phenyl ring.
  • a further configuration for R 7 include Ci-C 3 alkandiylaryl and Ci-C 3 alkanediylheterocyclyl, wherein the Ci-C3alkandiyl moiety is optionally substituted with Ci-C ⁇ alkyl.
  • Preferred configurations for the Ci-C ⁇ alkyl according to this embodiment include Ci-C4alkyl such as methyl or ethyl; haloCi-C 4 alkyl, such as trifluoromethyl and C 3 -C 4 cycloalkyl such as cyclopropyl.
  • the optional substituents to the aryl, heterocyclyl and alkyl moieties of R 7 are as defined above. Representative values include one or two substituents independently selected from Ci-C4alkyl such as methyl; halo such as fluoro; haloCi-C 4 alkyl such as fluoromethyl and trifluoromethyl; and cyano.
  • R 7 include a carbon chain which chain is optionally interrupted by one or two oxygen atoms and which length is 5, 6 or 7 atoms.
  • Preferred configurations for such a chain include Cs-Cyalkyl, Ci-C3alkoxy-Ci-C3alkoxy, such as methoxyethoxy, or Ci-C3alkoxy- Ci-C 3 alkyl, such as 3-methoxypropyl or 2-methoxyethyl
  • R 8 is as recited above, preferably hydrogen or methyl.
  • a further embodiment of the invention include compounds of formula (I) wherein R , 7 and R together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl group, for example optionally substituted pyrrole, piperidine or morpholine.
  • R 7 and R 8 are both Ci-C ⁇ alkyl, such as ethyl, propyl or butyl.
  • Link E between ring A and the unit CH(Y)(R 9 ) is as defined above.
  • the link E is -CH(Rc)-, -NRd- or -O-, in which case the compounds of the invention have one of the partial structures:
  • Rc, Rd, R 9 and Y are as defined above.
  • one of R 9 and Rc in formula Ha, one of R 9 and Rd in formula lib and R 9 in formula lie is a carbon chain which chain is optionally interrupted by one or two oxygen atoms and which length is 5, 6 or 7 atoms.
  • Preferred configurations for such a chain include Cs-Cyalkyl, Ci- C3alkoxy-Ci-C3alkoxy, such as methoxyethoxy, or Ci-C3alkoxy-Ci-C3alkyl, such as 3- methoxypropyl or 2-methoxyethyl.
  • the other one of Rc and R 9 in formula Ha and Ra and R 7 in formula lib is preferably hydrogen or methyl. It is to be understood that only stable configurations of the partial structures (Ha), (lib) and (lie) are contemplated.
  • E is -CH(Rc)-CH(Rc)-, -NRd-CH(Rd)-, CH(Rd)-NRd-, NRd-NRd-, -CH(Rd)-O- or -0-CHRd-, in which case compounds of the invention have the partial structures:
  • Rc, Rd, R 6 , R 9 and Y are as defined above.
  • one of the moieties Rc, Rd and R 9 in each of the above partial structures is a carbon chain which chain is optionally interrupted by one or two oxygen atoms.
  • the chain length is 5, 6 or 7 atoms.
  • Preferred configurations for such a chain include Ci-C3alkoxy- Ci-C3alkoxy, such as 2-methoxyethoxy, or Ci-C3alkoxy-Ci-C3alkyl, such as 3-methoxypropyl or 2-methoxyethyl. It is to be understood that only stable configurations of the partial structures (Ha), (lib) and (lie) are contemplated.
  • a currently preferred value for E according to this embodiment is -CHRc-CHRc- i.e. corresponding to partial structure (Hd), wherein one Rc is hydrogen or methyl and the other is hydrogen, Ci-CsalkoxyCi-C ⁇ alkoxy such as 2-methoxyethoxy or 3-methoxypropoxy.
  • R 9 is phenyl and Y is hydrogen.
  • a preferred embodiment of the invention includes compounds of formula (I) comprising any of the partial structures:
  • a further preferred value for E is -CH(Rd)-NRd-, i.e. corresponding to partial structure (Hf), wherein one of the Rd is Ci-C ⁇ alkyl or Ci-Csalkoxy-Ci-Csalkyl, such as 3-methoxypropyl or 2- methoxyethyl and the other is hydrogen or methyl.
  • Y is hydrogen, d-C ⁇ alkyl, Co-CsalkanediylCs-C ⁇ cycloalkyl, Co- Csalkanediylaryl or Co-C 3 alkanediylheterocyclyl, wherein each Ci-C ⁇ alkyl, cycloalkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from haloCi-C4alkyl, Ci-C4alkyl, Ci-C4alkoxy, hydroxy and cyano.
  • Preferred values for Y include hydrogen, Ci-C ⁇ alkyl especially methyl, ethyl or isopropyl; optionally substituted Co-C 3 alkanediylaryl or Co-C 3 alkanediylheterocyclyl, such as optionally substituted phenyl, optionally substituted benzyl or optionally substituted pyridyl.
  • the optional substituents to Y are as defined above.
  • Representative values include Ci-C4alkyl such as methyl; halo such as fluoro; haloCi-C 4 alkyl such as fluoromethyl and trifluoromethyl; and cyano.
  • the substituent(s) are conveniently in the para and/or ortho position.
  • favoured configurations for Y according to this embodiment include phenyl or pyridyl which is substituted in the para position.
  • the group W is bonded either directly to the amide nitrogen, i.e. q is 0, or W is bonded via a methylene or ethylene moiety, i.e. q is 1 or 2 respectively.
  • W is bonded directly to the amide nitrogen or via a methylene moiety, i.e. q is 0 or 1 respectively.
  • the moiety linking W to the amide nitrogen may be a 1,1-cyclopropyl group, in which case compounds of the invention have the partial structure:
  • Preferred compounds according to this embodiment include those wherein p is 0 and W is phenyl or substituted phenyl, as shown in the structure below:
  • W is hydrogen, Ci-C ⁇ alkyl, Cs-C ⁇ cycloalkyl, aryl or heterocyclyl which is optionally substituted with one, two or three substituents.
  • W is an optionally substituted mono or bicyclic aryl moiety such as phenyl or naphthyl, preferably optionally substituted phenyl.
  • W is an optionally substituted mono- or bicyclic ring containing 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur.
  • Representative monocyclic rings according to this embodiment include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like
  • representative bicyclic rings include quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl each of which is optionally substituted wherein each of the mono and bicyclic rings is optionally substituted.
  • W is a monocyclic optionally substituted 5- or 6-membered ring, such as optionally substituted phenyl.
  • the ring is preferably mono substituted with the substituent in the meta or para position.
  • the substituents are preferably in the two meta positions or in the meta and para positions.
  • Preferred optional substituents to W include one or two substituents independently selected form halo such as fluoro or chloro; C 3 -C 4 cycloalkyl such as cyclopropyl; haloCi-Csalkyl such as fluoromethyl and trifluoromethyl; Ci-C 4 alkyl such as methyl, ethyl and isopropyl.
  • halo such as fluoro or chloro
  • C 3 -C 4 cycloalkyl such as cyclopropyl
  • haloCi-Csalkyl such as fluoromethyl and trifluoromethyl
  • Ci-C 4 alkyl such as methyl, ethyl and isopropyl.
  • 'Ci_C 4 alkyl' as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-l -propyl, 2-methyl-2-propyl;
  • Ci-C 4 alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 2-methyl-l- butyl, 2-methyl- 1-pentyl, 2-ethyl-l -butyl, 3-methyl-2-pentyl, and the like.
  • Ci-C 6 alkyl is Ci-C 4 alkyl.
  • C 2 -C 6 alkenyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbon bonds and at least one carbon-carbon double bond, and having from 2 to 6 carbon atoms, such as, for example, ethenyl (or vinyl), 1- propenyl, 2-propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2- pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl and the like.
  • C 2 -Cealkenyl is C 2 -C 4 alkenyl.
  • C 2 -C 6 alkynyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbon bonds and at least one carbon-carbon triple bond, and having from 2 to 6 carbon atoms, such as, for example, ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like.
  • C 2 -Cealkynyl is C 2 -C 4 alkynyl.
  • C 3 -C n cycloalkyl means a non aromatic all carbon ring comprising 3 to n carbon atoms, wherein n is 3, 4 or 5, i.e. cyclopropyl, cyclobutyl or cyclopentyl.
  • the cycloalkyl may optionally be substituted with one or two substituents independently selected from Ci-C3alkyl, C 2 - Csalkenyl, C 2 -C 3 alkynyl and halo.
  • 'C 0 -C 3 alkanediyl' defines a bond (Co) or a bivalent straight or branched saturated hydrocarbon chain having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1 ,2-propanediyl, and the like, especially methylene.
  • 'C 2 -C 3 alkenediyl' defines a bivalent straight or branched hydrocarbon chain having one double bond and having 2 or 3 carbon atoms such as, for example, ethenylene, 1,3-propenediyl, 1 ,2-propenediyl, and the like, especially vinylene.
  • 'C 2 -C 3 alkynediyl' defines a bivalent hydrocarbon chain having 2 or 3 carbon atoms and a triple bond, i.e. ethynylene and propynylene.
  • Ci-C ⁇ alkoxy means a radical O-Ci-C ⁇ alkyl wherein Ci-C ⁇ alkyl is as defined above.
  • Ci-C ⁇ alkoxy of interest include but are not limited to methoxy, ethoxy n-propoxy and isopropoxy.
  • 'halo' is generic to fluoro, chloro, bromo and iodo. Fluoro is typically preferred in many applications.
  • 'haloCi-C4alkyl' as a group or part of a group, is meant to include mono- and polyhalo substituted Ci-C4alkyl, in particular Ci-C4alkyl substituted with one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Preferred is trifluoromethyl.
  • the halogen atoms may be the same or different.
  • Ci-C ⁇ alkyl as a group or part of a group, unless the context suggests otherwise, includes NH 2 , NHCi-C ⁇ alkyl or N(Ci-C6-alkyl)2, wherein in the amino definitions each Ci-C ⁇ alkyl is especially Ci-C4alkyl variants. Included are also radicals wherein the two Ci-C ⁇ alkyl groups of the N(C 1 - C ⁇ -alkyFh together with the nitrogen atom to which they are attached form a saturated cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • 'Co-C 3 alkanediylaryl' as applied herein is meant to include an aryl moiety such as a phenyl or naphthyl or a phenyl fused to a Cs-C ⁇ cycloalkyl (for example indanyl), or a Cs-C ⁇ cycloalkenyl which aryl is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1,2- propanediyl or 1,3-propanediyl group as defined for Ci-C3alkanediyl above.
  • aryl moiety such as a phenyl or naphthyl or a phenyl fused to a Cs-C ⁇ cycloalkyl (for example indanyl), or a Cs-C ⁇ cycloalkenyl which aryl is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1,2- propanediyl or 1,3-propaned
  • Suitable aryl groups include but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indenyl and indanyl. Unless otherwise indicated the aryl and/or its fused cycloalkyl moiety is optionally substituted with one, two or where valence allows three substituents independently selected from Ci-C4alkyl (optionally substituted with one or two substituents independently selected from Co- C 3 alkanediylaryl*, amino, carbamoyl, amido and Ci-C4alkoxyamido), C 2 -C6alkenyl, C 2 - C 6 alkynyl, C 3 -C 6 cyclolkyl, Ci-C 4 alkoxy, Ci-C 4 alkoxyCi-C 3 alkyl, Ci-C 4 alkoxyCi-C 6 alkoxyC 0 - C 3 alkyl, halo, haloCi-C 4 alkyl, polyhaloC
  • 'C 2 -C 3 alkenediylaryl and 'C 2 -C 3 alkynediylaryl have the corresponding meanings, adjusted just for the link to the aryl moiety as defined for 'C 2 -C 3 alkenediyr and 'C 2 -C 3 alkynediyl
  • 'Co-C 3 alkanediylheterocyclyl' as applied herein is meant to include a 5-6 membered saturated, partly unsaturated or unsaturated heterocyclic ring containing 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulphur, the ring being optionally fused with a benzene ring.
  • heterocyclyl groups include but are not limited to pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, thiazolidinyl, thiadiazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, azetidinyl, piperidinyl,
  • Ci-C 4 alkyl optionally substituted with one, two or where valence allows three substituents independently selected from Ci-C 4 alkyl (optionally substituted with one or two substituents independently selected from Co-C 3 alkanediylaryl*, amino, carbamoyl, amido and Ci- C4alkoxyamido), C2-Cealkenyl, C2-Cealkynyl, Cs-C ⁇ cyclolkyl, Ci-C4alkoxy, Ci-C4alkoxyCi- C 3 alkyl, Ci-C 4 alkoxyCi-C 6 alkoxyCo-C 3 alkyl, halo, haloCi-C 4 alkyl, polyhaloCi-C 4 alkyl, hydroxy, hydroxyCi-C4alkyl, amino, aminoCi-C4alkyl, carb
  • 'C 2 -C 3 alkenediylheterocyclyl and 'C 2 -C 3 alkynediylheterocyclyl have the corresponding meanings, adjusted just for the link to the heterocyclyl moiety as defined for 'C 2 -C 3 alkenediyr and 'C 2 -C 3 alkynediyl
  • Heteroaryl' as applied herein means an aromatic heterocyclyl moiety.
  • aryl and heterocyclyl moieties within the scope of the above definitions are thus a monocyclic ring with 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a 6 membered ring fused to a 5 or 6 membered ring.
  • Cycloalkyl' as applied herein is meant to include a C 3 -Cecycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, which is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1 ,2-propanediyl or 1,3- propanediyl group as defined for Ci-C3alkanediyl above.
  • the cycloalkyl group may contain an unsaturated bond.
  • the cycloalkyl moiety is optionally substituted with 1-3 substituents selected from Ci-C4alkyl (optionally substituted with one or two substituents independently selected from Co-C3alkanediylaryl , amino, carbamoyl, amido and C 1 - C4alkoxyamido), C2-Cealkenyl, C 2 -Cealkynyl, Cs-C ⁇ cyclolkyl, Ci-C4alkoxy, Ci-C4alkoxyCi- C 3 alkyl, Ci-C 4 alkoxyCi-C6alkoxyC 0 -C 3 alkyl, halo, haloCi-C 4 alkyl, polyhaloCi-C 4 alkyl, hydroxy, hydroxyCi-C4alkyl, amino, aminoCi-C4alkyl, carbamoyl, amido, cyano, azido, nitro, Ci-C ⁇ alkylcarbonyl, a
  • 'C 2 -C 3 alkenediylC3-C7carbocyclyl and 'C 2 -C 3 alkynediylC3-Cvcarbocyclyl have the corresponding meanings, adjusted just for the link to the carbocyclyl moiety as defined for 'C 2 -C 3 alkenediyl' and 'C 2 -C 3 alkynediyl
  • radical positions on any molecular moiety used in the definitions may be anywhere on such a moiety as long as it is chemically stable.
  • Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated.
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl
  • pentyl includes 1- pentyl, 2-pentyl and 3-pentyl.
  • each definition is independent.
  • esters prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy and/or a carboxyl group.
  • An in vivo hydrolysable ester is an ester, which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci-C ⁇ alkoxymethyl esters for example methoxymethyl, Ci-C ⁇ alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, Cs-CscycloalkoxycarbonyloxyCi-C ⁇ alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci-C ⁇ alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxy ethyl which may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydro lysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N- alkylcarbamoyl (to give carbamates), dialkylamino acetyl and carboxyacetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
  • salts of the compounds of formula (I) or any subgroup of compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulphuric, nitric, phosphoric acids and the like; or organic acids such as, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • butanedioic acid maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulphonic, ethanesulphonic, benzenesulphonic, /?-toluenesulphonic, cyclamic, salicylic, /?-amino salicylic, pamoic acids and the like.
  • Acid addition salt forms can be converted to the free base form by treatment with an appropriate base.
  • the compounds of formula (I) containing an acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with an appropriate organic or inorganic base.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, JV-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • Base addition salt forms can be converted to the free acid form by treatment with an appropriate acid.
  • addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) or any of the subgroups of compounds of formula (I), as well as the salts thereof, are able to form.
  • Such solvates are for example hydrates, alcoholates and the like.
  • 'quaternary amine' as used above and hereinafter defines the quaternary ammonium salts which the compounds of formula (I) or any of the subgroups of compounds of formula (I), are able to form by reaction between a basic nitrogen of a compound of formula (I) or any of the subgroups of compounds of formula (I), and an appropriate quaternizing agent, such as, for example, an optionally substituted alkyl halide, aryl halide or arylalkyl halide, e.g. methyl iodide or benzyl iodide.
  • an appropriate quaternizing agent such as, for example, an optionally substituted alkyl halide, aryl halide or arylalkyl halide, e.g. methyl iodide or benzyl iodide.
  • reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulphonates, alkyl methanesulphonates, and alkyl p-toluenesulphonates.
  • a quaternary amine has a positively charged nitrogen.
  • Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
  • iV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called iV-oxide.
  • the compounds according to the invention may contain one or more asymmetrically substituted carbon atoms, asymmetric or chiral centre.
  • the presence of one or more of these asymmetric centres in compounds according to the invention can give rise to stereochemically isomeric forms, stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, both in pure form and mixed with each others, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
  • stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates.
  • the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e.
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by application of art-known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, pp 104-107).
  • enantiomers may be separated from each other using known procedures including, for example, formation of diastereomeric mixtures by reaction with a convenient optically active auxiliary species followed by separation of the diastereomers, using for instance selective crystallisation, and finally cleavage of the auxiliary species.
  • optically active auxiliary species are optically active acids and bases such as tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulphonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecif ⁇ cally.
  • the compound When a specific stereoisomer of a compound is desired, the compound will preferably be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the compounds of formula (I) may have metal binding, chelating or complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
  • the invention relates to the compounds of formula (I) or any subgroup of compounds of formula (I) per se, the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof.
  • One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the iV-oxides, salts, as the possible stereoisomeric forms thereof.
  • the invention further relates to methods for the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I), the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, its intermediates, and the use of the intermediates in the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I).
  • the invention also relates to the use of a compound of formula (I) or any subgroup of compounds of formula (I), or an prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof, for the manufacture of a medicament.
  • the invention relates to the use of a of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof in therapy.
  • the term 'therapy' also includes 'prophylaxis' unless there are specific indications to the contrary.
  • the terms 'therapeutic' and 'therapeutically' should be construed accordingly.
  • the compounds of formula (I) or any of the subgroups of formula (I) have enzyme inhibiting properties, in particular they are inhibitors of aspartyl proteases such as renin and BACE.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a compound of any of the subgroups of formula (I) or a pharmaceutically acceptable salt thereof as specified herein, and a pharmaceutically acceptable adjuvant, diluent or carrier for administration to a subject in need thereof.
  • a therapeutically effective amount in this context is an amount sufficient to act in a prophylactic way against, to stabilize or to reduce adverse conditions associated with RAS activity, such as or related to hypertension, heart failure, pulmonary hypertension, renal insufficiency or renal ischemia, or to act in a prophylactic way against or to stabilize conditions associated with BACE activity such as Alzheimer's disease in affected subjects or subjects being at risk of being affected.
  • the invention further relates to a process of preparing a medicament or a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable adjuvant, diluent or carrier with a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) as specified herein, or a pharmaceutically acceptable salt or a solvate, prodrug, N-oxide, quaternary amine, metal complex or stereochemically isomeric form thereof as specified herein.
  • the invention relates to use of the compounds of formula (I) in the treatment and/or prophylaxis of diseases such as or related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, restenosis post angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments with immunosuppressive agents, and other diseases known to be related to the renin-angiotensin system.
  • diseases such as or related to hypertension, congestive heart failure, pulmonary hypertension, renal insuff
  • the invention relates to a method for the treatment and/or prophylaxis of diseases or conditions which are associated with a dysregulation of the renin-angiotensin system, in particular to a method for the treatment or profylaxis of the above mentioned diseases, said method comprising administering to a patient a pharmaceutically active amount of a compound of formula (I) or any of the subgroups of formula (I).
  • the invention further provides a method of treating a disease or condition known to be related to the renin-angiotensin system (e.g. hypertension) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, iV-oxide, quaternary amine, metal complex, or stereochemical ⁇ isomeric form thereof, as hereinbefore defined.
  • a disease or condition known to be related to the renin-angiotensin system e.g. hypertension
  • the invention further provides a method of treating diseases or conditions such as or related to the above mentioned (e.g. hypertension) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined.
  • diseases or conditions such as or related to the above mentioned (e.g. hypertension) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined.
  • the compounds of the present invention are also useful for the inhibition of BACE activity. Accordingly, a further embodiment of the invention relates to use of the compounds of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined in the treatment and/or prophylaxis of Alzheimer's disease by inhibiting the activity of BACE.
  • the compounds of the present invention have also utility in treating, ameliorating, controlling or reducing the risk of Alzheimer's disease.
  • the compounds may be useful for the prevention of dementia of the Alzheimer's type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer's type.
  • the compounds may also be useful in treating, ameliorating, controlling or reducing the risk of diseases mediated by abnormal cleavage of amyloid precursor protein (also referred to as APP), and other conditions that may be treated or prevented by inhibition of ⁇ -secretase.
  • APP amyloid precursor protein
  • Such conditions include mild cognitive impairment, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic! lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, Down syndrome, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes and atherosclerosis.
  • the invention relates to a method for the treatment and/or prophylaxis of diseases or conditions which are associated with activity of BACE, in particular to a method for the treatment or prophylaxis of the above mentioned diseases, said method comprising administering to a patient a pharmaceutically active amount of a compound of formula (I) or any of the subgroups of formula (I).
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of formula I/salt/so lvate (active ingredient) may be in the range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary.
  • unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
  • the compounds of formula (I) and pharmaceutically acceptable salts, solvates, prodrugs, TV-oxides, quaternary amines, metal complexes, or stereochemically isomeric forms thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound of formula (I) /salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w/w, of active ingredient, and, from 1 to 99.95 %w/w, more preferably from 30 to 99.90 %w/w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
  • a representative tablet within the scope of the pharmaceutical composition of the invention could have a mass of 500 - 1500 mg with a loading of active ingredient in the range 35 - 75%, with the balance being excipients, such as binders, disintegrants, antioxidants and the like.
  • compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • the oral delivery route, particularly capsules or tablets is favoured.
  • the pharmaceutical composition of this invention may also contain, or be co- administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more of the diseases or conditions referred to hereinabove.
  • the compounds of the present invention may be used in combination with one or more other pharmacological agents that treat, prevent, control ameliorate or reduce the risk for side effects or toxicity of the compounds of the present invention.
  • Such other pharmacological agents may be administered, by route and in amount commonly used therefore, contemporaneously or sequentially with the compounds of the present invention.
  • the pharmaceutical compositions of the present invention include those that contain one or more active ingredients, in addition to the compounds of the present invention.
  • the combination may be administered as part of a unit dosage form combination product, or as a kit or a treatment protocol wherein one or more additional pharmacological agents are administered in separate dosage forms as a part of a treatment regimen.
  • Representative examples of pharmacologically active agents directed to combinations with the compounds of the present invention useful for the treatment and/or the prophylaxis of adverse conditions associated with RAS activity as described hereinabove include ACE- inhibitors, neutral endopeptidase inhibitors, aldosterone antagonists, angiotensin II receptor antagonists, endothelin receptors antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholitics, beta- adrenergic antagonists, alpha-adrenergic antagonists and/or other drugs beneficial for the prevention or the treatment of the above-mentioned diseases such as 1 ibeta-hydroxy steroid dehydrogenase type 1 inhibitors and soluble guanylate cyclase activators.
  • ACE- inhibitors neutral endopeptidase inhibitors
  • aldosterone antagonists angiotensin II receptor antagonists
  • endothelin receptors antagonists vasodilators
  • calcium antagonists potassium activ
  • the present invention is also directed to combinations of the compounds of the invention with one or more pharmacologically active agents useful in the treatment and/or the prophylaxis of Alzheimer's disease.
  • combinations include combinations with anti- Alzheimer's agents, for example other BACE inhibitors or ⁇ -secretase inhibitors; HMG-CoA reductase inhibitors; NSAIDs including ibuprofen; vitamin E; anti-amyloid antibodies, including anti- amyloid humanized monoclonal antibodies; CB-I receptor antagonists or CB- 1 receptor inverse agonists; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H3 antagonists; AM
  • the compounds of the present invention and intermediates useful for the synthesis of these compounds are prepared by methods and techniques known to those skilled in the art.
  • the general schemes below illustrate typical synthetic routes to the compounds of the invention and to intermediates thereof.
  • Alternative routes which will be readily apparent to the ordinary skilled organic chemist, may alternatively be used to synthesize various portions of the molecules as illustrated by the general schemes and the preparative examples below.
  • Scheme 1 illustrates a synthetic route to a lactone which is a useful intermediate in the preparation of compounds of formula (I).
  • the isopropylidene derivative (Ia) achieved for example as described in Tetrahedron lett, 1987, 28, 1143, can be transferred into the methyl glycoside (Ib) by acidic hydrolysis of the acetal group effected by treatment with a suitable acid such as sulphuric acid, in the presence of methanol.
  • the achieved free secondary hydroxy group can then be reductively removed for instance by transformation of the hydroxy group into a thiocarbonyl group by reaction with thiocarbonyl diimidazole (TCDI) followed by reduction of the formed thiocarbonyl group using for instance tributyltin hydride in the presence of a radical initiator like azobis-(2- methylpropyonitrile) (AIBN) or the like, to give the 2,3-dideoxy glycoside (Ic).
  • a radical initiator like azobis-(2- methylpropyonitrile) (AIBN) or the like
  • Oxidative cleavage of the methyl ether can be performed for example by oxidation with m- chloroperbensoesyra or the like in the presence of BF3-etherate, which gives the lactone (Id).
  • a substituent in the position ⁇ to the carbonyl can then be introduced for example by treatment of the lactone (Id) with a base such as LDA or equivalent, followed by reaction with a suitable alkylating agent such as an alkyl halide like an alkyl bromide or alkyl iodide or a derivative of sulphonic acid such as a mesylate, triflate or tosylate or the like, thus providing the alkylated lactone (Ie).
  • a suitable alkylating agent such as an alkyl halide like an alkyl bromide or alkyl iodide or a derivative of sulphonic acid such as a mesylate, triflate or tosylate or the like, thus providing the alkylated lactone (Ie).
  • a suitable alkylating agent such as an alkyl halide like an alkyl bromide or alkyl iodide or a derivative of sulphonic acid such as a mes
  • Lg is a leaving group
  • the primary hydroxy group of the lactone (If) can be selectively alkylated for example by activation with dibutyltin oxide followed by reaction with a desired alkylating agent Q-CH 2 Lg wherein Lg is a suitable leaving group such as a halide like bromide or iodide in the presence of tetrabutylammonium bromide or the like thus forming the ether derivative (2a).
  • the substituent Q-CH 2 can be introduced by using the Mitsunobu conditions (Mitsunobu, 1981, Synthesis, January, 1-28; Rano et al, Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak et al, Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter et al., Tetrahedron Lett., 1994, 35, 27, 4705- 4706) i.e. reaction of the primary hydroxy group of the diol (If) with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine followed by displacement with a desired alcohol.
  • Replacement of the secondary hydroxy group of the alcohol (2a) by azide may be effected by transforming the hydroxy group to a leaving group, for example a derivative of sulphonic acid like a triflate or tosylate or the like by subjecting the alcohol to sulphonylating conditions such as treatment with the appropriate anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the leaving group with azide for example sodium azide, thus giving the azide derivative (2b).
  • the linear amino compound (2e) can then be achieved by opening of the lactone with a desired amino derivative (2c) in the presence of for example 2-hydroxypyridine and a base like isopropyl diethylamine.
  • Lactones useful for the synthesis of compounds of formula (I) wherein Z is S or NH and n is 1, can be prepared from the diol If for example by a Mitsunobu reaction with a thiol or amino derivative respectively, as illustrated in scheme 2B.
  • an azide derivative such as sodium azide or DPPA in the Mitsunobu reaction with the alcohol (2a
  • An alternative method to obtain the amino derivative (2Bc) is to selectively oxidize the primary hydroxy group of the alcohol (If) to the corresponding aldehyde, effected for example by treatment with Dess-Martin periodinane or by any other suitable oxidation reagent, followed by a reductive amination with the desired amino derivative Q-CH 2 - NHRa in the presence of a reducing agent like NaCNBH 3 . Replacement of the secondary hydroxy group with azide, opening of the lactone and finally reduction of the azide as described above, then provides the linear amines (2Bd and 2Be).
  • Intermediates for the preparations of compounds of formula (I) wherein the group Q is linked directly to a sulphur or nitrogen atom, i.e. Z is S or NRa and n is 0, may be prepared by transformation of the primary hydroxy group of the diol (2a) into a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with a desired thiol Q-SH or a amine Q-NHRa optionally in the presence of a base.
  • a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like
  • a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the
  • An alternative method for the preparation of compounds wherein Z is S and n is 0 is to react the diol (2a) with a desired diphenyl disulphide derivative in the presence of nBu 3 P.
  • Compounds wherein Z is NRa and n is 0 may alternatively be achieved by oxidation of the primary hydroxy group of the diol (2a) followed by a reductive amination with a desired aniline derivative Q-NRa in the presence of a suitable catalyst like NaCNBH 4 or the like.
  • the oxidation can be performed either at the last step of the synthesis or on any suitable intermediate.
  • Many suitable methods for this oxidation are described in the literature for example, a peroxyacid such as AcOOH, mCPBA can be used.
  • Amino derivatives used for the opening of the lactone in scheme 2 are available commercially or they can easily be prepared by the skilled person according to literature procedures.
  • the lactone 2b in scheme 2 is opened with the appropriate amino amide, which is conveniently prepared from the corresponding amino acid for example as illustrated in scheme 3.
  • the amino acid (3a), carrying the desired side chain R 4 and R 4 can be coupled to the amine W- (CH2) q -NH2 using any convenient method for peptide coupling known in the art.
  • a coupling agent like HATU or isobutylchloro formate in the presence of a tertiary amine such as ethyldiisopropylamine (DIEA) or N-methylmorpholine in a solvent like dimethyl formamide can be used.
  • DIEA ethyldiisopropylamine
  • N-methylmorpholine in a solvent like dimethyl formamide
  • the azide derivative (4a), prepared for example as outlined in scheme 1, wherein Pg is a hydroxy protecting group for example a benzyl group can be transformed to the corresponding amine by reduction of the azide using any convenient reduction method such as hydrogenation in the presence of a suitable catalyst, such as Lindlar's catalyst or the like in the presence Of BoC 2 O to provide the boc protected amino derivative (4b). Protection of the secondary hydroxy group, using a protecting group (Pg 2 ) which is orthogonal to the one used for the primary hydroxy group (Pg 1 ), followed by removal of the primary hydroxy protecting group using the appropriate conditions according to the group used, such as for example catalytic hydrogenation in the case of a benzyl group, provides the primary alcohol (4c).
  • Suitable protecting groups for the above route will be recognized by the skilled person and a numerous of useful protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981).
  • benzyl can be used as Pg 1 and acetyl as Pg 2 .
  • the group CH 2 -Q can then be introduced as described above.
  • Trichloroacetimidates are conveniently prepared by reaction of the corresponding alcohol with trichloroacetonitrile in the presence of a base like NaH.
  • Compounds of formula (I) wherein n is 1 and Z is O, S or NRa may be prepared by a Mitsunobu reaction of the primary alcohol (4c) with a desired alcohol, Q-CH 2 )-0H, thiol, Q-CH 2 -SH or amine Q-(CH 2 ) n -NHRa respectively.
  • An alternative method for the preparation of compounds wherein Z is S and n is O is to react the alcohol (4a) with a desired derivative of diphenyl disulphide in the presence of 11BU3P.
  • Compounds wherein Z is NRa and n is O may alternatively be achieved by oxidation of the hydroxy group of the alcohol (4a) followed by a reductive amination with a desired aniline derivative Q-NRa in the presence of a suitable catalyst like NaCNBH 4 or the like. Removal of the Boc group according to standard procedures such as treatment with an acid, for example TFA, followed by removal of the hydroxy protecting group using the appropriate conditions, then provides the amine (4e).
  • Scheme 5 illustrates a method to prepare a substituted phenyl derivative useful for the preparation of compounds of formula (I) wherein Q is phenyl substituted with amino methyl or amido methyl and derivatives thereof.
  • the hydroxy protected cyanobenzyl derivative (5 a) is conveniently be prepared by protection of commercially available cyanobenzyl alcohol, illustrated herein as 3 -cyanobenzyl alcohol, with a suitable protecting group, for example a trityl or monomethoxy trityl group using standard conditions well known in the art.
  • the afforded alcohol (5c) can then be used in the coupling to the primary alcohol of the lactone If or the linear compound 4c employing for example the Mitsunobu conditions as described in scheme 2 and 4 respectively.
  • the hydroxy group of the alcohol (5c) can be transformed into a leaving group such as a bromide for example by treatment with bromine or carbontetrabromide in the presence of triphenylphosphine or the like thus affording the bromoderivative (5d), or the hydroxy group can be transformed into a derivative of sulphonic acid by reaction with a suitable sulphonylating agent such as a sulphonic halide or anhydride optionally in the presence of a base for example pyridine.
  • the afforded compound can then be coupled to the primary alcohol of the lactone If or the linear compound 4c by way of a displacement reaction.
  • Scheme 6 illustrates an example to another substituted phenyl derivative, useful for the preparation of compounds of formula (I) wherein Q is phenyl substituted with an alkoxy-alkoxy group.
  • Scheme 7 shows an alternative route to compounds of the invention, starting from Garner's aldehyde.
  • the group Q-(CH 2 )D can then be introduced using any suitable method such as any of those described above. For example, a trichloroimidate of the desired group Q-(CH 2 ) n in the presence of TMS triflate will provide the ether derivative (7f) i.e. Z' is O.
  • the lactone may then be opened either directly with a desired amine as described above to give the amide (7h), or alternatively, the lactone may be opened by treatment with hydroxide such as lithium hydroxide, thus affording the acid (7g). Protection of the hydroxy group, using any conventional protecting group for example a silyl group such as a tert.butyl dimethylsilyl group, followed by coupling of the acid to a suitable amine using standard peptide coupling conditions such as using a coupling agent like EDAC in the presence of HOBt and a tertiary amine like triethylamine, and finally removal of the hydroxy protecting group provide the amide (7h).
  • any conventional protecting group for example a silyl group such as a tert.butyl dimethylsilyl group
  • coupling of the acid to a suitable amine using standard peptide coupling conditions such as using a coupling agent like EDAC in the presence of HOBt and a tertiary amine like triethyl
  • the free hydroxy group of compound (4a) can be replaced by two fluoro atoms by oxidizing the hydroxy group to a keto group using any convenient method such as using a reagent like Dess Martin periodinane or oxone® (potassium monopersulphate triple salt) or any other suitable oxidizing agent, followed by treatment of the afforded keto compound with a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane, to give the difluoro compound (8a).
  • a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane
  • the monofluoro compound (8c) with the desired stereochemistry can be obtained by first inverting the stereochemistry at the steric centre whereto the hydroxy group is attached and thereafter replace the hydroxy group with fluorine, effected for example by subjecting the afforded inverted alcohol to fluorinating conditions such as treatment with DAST or Deoxofluor in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable fluorinating conditions.
  • Inversion of the stereochemistry of the alcohol (4a) can be performed for example by subjecting the alcohol to a Mitsunobu reaction with for instance p-nitrobenzoic acid and reagents like DIAD and Ph 3 P followed by hydrolysis of the afforded p-nitrobenzoic ester by for example treatment with sodium methoxide or the like.
  • Scheme 8 illustrates the replacement of the hydroxy group with fluoro or difluoro as the last step of the synthesis, the skilled person will realise that this transformation alternatively may be performed at any other suitable stage of the synthesis for example on any of the intermediates described above.
  • Pg is an N-protecting group
  • the configuration of compound (9a), prepared as described above has to be inverted, for example as described in scheme 8.
  • the inverted alcohol (9b) can then be subjected to Mitsunobu conditions, i.e.
  • azido derivative (9c) can alternatively be achieved by transformation of the hydroxy group to a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloro methane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with sodium azide or the like.
  • the compounds of the invention are then achieved by coupling of a suitable amine such as any of those described above, to an acid as schematically outlined in scheme 10.
  • Coupling of a desired amino derivative (10a) to a suitable acid (10b or 10b') can be performed using standard peptide coupling techniques which are well known by a person skilled in the art.
  • a coupling agent like HATU or the like can be used in the presence of a tertiary amine like diisopropylethylamine or the like in a solvent like DMF to provide the amide (10c or 10c').
  • Acids (10b) to be used in the coupling with the amine (10a) are available commercially or from the literature, or they can be prepared as outlined herein below. Acids (10b), wherein ring A is phenyl and E is CHRc-CHRc, can be prepared as shown in scheme 11.
  • X is a leaving group, e.g. Br
  • Rc' is C r C 6 alkyl, C r C 6 alkoxyC-
  • Acids (10b) wherein ring A is phenyl, E is -NRd-CH(Rd)- can be prepared as illustrated in scheme 12.
  • Scheme 13 illustrates a route to acids (10b) wherein E is -0-CH(Rd)- and Rd is hydrogen, and also an alternative route to acids wherein E is NRd-CHRd-.
  • X is a leaving group, e.g. Br
  • Ether derivatives (13d) can then be achieved by hydrolysis of the methyl ester by treatment with sodium hydroxide or the like, followed by alkylation of the secondary hydroxy group using any desired alkylating agent (13c) wherein X is a leaving group such as bromide, iodide or chloride in the presence of a base like sodium hydride.
  • Amino derivatives (13f) can be achieved by subjecting the alcohol (13b) to a Mitsunobu reaction with a desired amine (13e), followed by hydrolysis of the methyl ester as described above.
  • sulphonylation of the amino group using any desired sulphonylating agent such as a sulphonylchloride, for example mesyl chloride or the like in the presence of pyridine in a solvent like dichloro methane or the like, optionally followed by alkylation of the nitrogen which can be effected by a displacement reaction with a desired alkylating agent Ra-X, wherein X is a leaving group such as a halide like bromide or iodide in the presence of a base like sodium hydride or the like, affords sulphone amide derivative (14d).
  • a sulphonylchloride for example mesyl chloride or the like in the presence of pyridine in a solvent like dichloro methane or the like
  • alkylation of the nitrogen which can be effected by a displacement reaction with a desired alkylating agent Ra-X, wherein X is a leaving group such as a halide like bromide
  • Useful sulphamoyl chlorides can be prepared for example as described by W. L. Matier et al. in J. Med. Chem. 1972, 15, 4, 538-541.
  • the diamino benzoic acid derivative (15a) can be achieved for example by removal of the fmoc group from commercially available boc-3-amino-5-(fmoc-amino)benzoic acid using standard conditions such as treatment with piperidine or morpholine or the like. Alkylation of the free amine effected for example by reaction with a desired aldehyde or ketone (15b) in the presence of a reducing agent like NaCNBH 3 or the like provides the amino derivative (15c).
  • the amine (15a) can be alkylated by reaction with an alkylating agent (15d) wherein X is a leaving group such as a halide like bromo or chloro or a derivative of sulphonic acid like a triflate or mesylate or the like, optionally in the presence of a base, which provides the amine (15e). Alkylation of the acid followed by removal of the boc group, introduction of the sulphone amide group and finally hydrolysis of the ester as described above, then provides the acid (15c).
  • an alkylating agent wherein X is a leaving group such as a halide like bromo or chloro or a derivative of sulphonic acid like a triflate or mesylate or the like, optionally in the presence of a base, which provides the amine (15e).
  • the bicyclic lactone (16a) prepared from the commercially available diester 3,4- bis(methoxycarbonyl)cyclopentanone as described in WO2005/073195, can be opened by treatment with a base, such as potassium carbonate or lithium hydroxide or the like to provide the diester (16b). Conversion of the hydroxy group into an amino group can then be performed using any convenient procedure whereof many are described in the literature, for example the Mitsunobu conditions may be employed i.e.
  • butyl group by subjecting the diester to acidic conditions like trifluoroacetic acid and triethylsilane in a solvent like methylene chloride then provides the acid (16e).
  • acidic conditions like trifluoroacetic acid and triethylsilane in a solvent like methylene chloride
  • Reduction of the acid for example by a two step process of Weinreb amide formation brought about by reaction with N,O- dimethylhydroxylamine in the presence of sodium hydrogencarbonate and subsequent Dibal reduction, gives the corresponding aldehyde (16f).
  • the afforded aldehyde can then be reacted as described above in order to get various acids which subsequently can be coupled to a desired amino derivative as described above.
  • X is a leaving group, e.g. Br or I
  • the bicyclic lactone (18a), prepared from the commercially available diester 3,4- bis(methoxycarbonyl)cyclopentanone as described in WO2005/073195 can be opened by treatment with a base, such as potassium carbonate or lithium hydroxide or the like to provide the diester (18b). Conversion of the hydroxy group into an amino group can then be performed using any convenient procedure whereof many are described in the literature. For example the Mitsunobu conditions may be employed i.e.
  • any functional groups present on any of the constituent compounds used in the preparation of the compounds of the invention are appropriately protected where necessary.
  • functionalities on the natural or non-natural amino acids are typically protected as is appropriate in peptide synthesis.
  • Suitable protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981) and “The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), the disclosure of which are hereby incorporated by reference.
  • Tributyltin hydride (5.18 g, 17.79 mmol) was dissolved in dry toluene (35 mL) under N 2 - atmosphere and refluxed for 5 minutes.
  • Compound Ib (5.56 g, 11.86 mmol) dissolved in dry toluene (35 mL) was added drop wise to the solution during 30 min. The combined solution was stirred at 110 0 C and after 2 hours the mixture was concentrated. Purification by flash column chromatography (toluene/ethyl acetate 18:1) gave the title compound (2.94 g, 72%).
  • the methyl-glycoside Ic (2.79 g, 8.16 mmol) was dissolved in dry CH 2 Cl 2 (50 rnL) and cooled to 0 0 C in an ice bath.
  • BF 3 OEt (0.52 rnL, 2.04 mmol) and m-chloroperbenzoic acid (2.20 g, 9.79 mmol) were added to the solution and the mixture was kept at 0 0 C for 2 hours before it was allowed to reach room temperature. After 4 hours the mixture was concentrated and extracted with ethyl acetate (3 x 50 mL) and saturated NaHCO 3 (50 mL). The combined organic layers were dried, filtered and concentrated. The crude residue was purified by flash column chromatography (toluene/ethyl acetate 18:1) to yield the title lactone (2.66 g, quant.) as white crystals.
  • the lactone Id (1.31 g, 4.01 mmol) was dissolved in dry THF (40 mL) and cooled to -78 0 C. After 15 min a solution of 2.0 M LDA (2.47 mL, 4.01 mmol) was added drop wise. After 30 min at -78 0 C methyl iodide (2.5 mL, 40.1 mmol) dissolved in dry THF (5 mL) was slowly added. After further 2 hours at -78 0 C the reaction was allowed to attain room temperature and quenched with saturated ammonium chloride (4 mL). The mixture was diluted with H 2 O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried, filtered and concentrated. Purification by flash column chromatography (toluene/ethyl acetate 18:1) gave the title compound (899 mg, 66%).
  • Boc- VaI-OH 500 mg, 2.30 mmol
  • benzylamine 321 mg, 2.99 mmol
  • DIPEA 0.52 mL
  • the title compound (27 mg, 77%) was synthesized by coupling of amine 2d (20 mg, 0.044 mmol) to 5-methanesulphonyl-methyl-amino)-N'-(l-phenyl-ethyl)-isophthalic acid according to the method described for the preparation of compound 11.
  • the title compound (13 mg, 17%) was synthesized by coupling the amine 3b (36 mg, 0.105 mmol) to 5-methanesulphonyl-methyl-amino)-N'-(l-phenyl-ethyl)-isophthalic acid according to the method described for the preparation of compound 11.
  • Compound 31 was collected as white powder after lyophilization.
  • the title compound (188 mg, 88%) was prepared by opening of the lactone Ih (152 mg, 0.49 mmol) according to the method described for the preparation of compound 2c but using the amine 4-fluorobenzylamine instead of the amine (5)-2-Amino- ⁇ /-benzyl-3-methyl-butyramide. The title compound was collected as white crystals after purification.
  • the title compound (18 mg, 52%) was prepared by coupling of amine Ik (25 mg, 0.051 mmol) to 5-(methanesulphonyl-methyl-amino)- ⁇ /-methyl-isophthalamic acid according to the method described for the preparation of compound 11.
  • the title compound was collected as white powder after lyophilization.
  • the title compound (94 mg, 70%) was synthesized by opening of the lactone 6c-(R) (77 mg, 0.26 mmol) with the amine Ii according to the method described for the preparation of compound 2c.
  • the title compound was collected as crystals after purification by flash column chromatography (toluene/ethyl acetate 1 :1).
  • the title compound (77 mg, 82%) was synthesized by reduction of the azide of compound 6d (97 mg, 0.19 mmol) according to the method described for the preparation of compound Ik.
  • the title compound was collected as a white powder after purification.
  • the title compound (34 mg, 74%) was synthesized by coupling of the amine 6e (26 mg, 0.055 mmol) with 5-methanesulphonyl-methyl-amino)-N'-(l-phenyl-ethyl)-isophthalic acid according to the method described for the preparation of compound 11.
  • the title compound was collected as a white powder after lyophilization.
  • the title compound (93 mg, 62%) was synthesized by opening of the lactone 6c-(5) (86 mg, 0.29 mmol) with the amine Ii according to the method described for the preparation of compound 2c.
  • the title compound was collected as crystals after purification by flash column chromatography (toluene/ethyl acetate 1 :1).
  • the title compound (66 mg, 99%) was synthesized by reduction of the azide of compound 7a (70 mg, 0.14 mmol) according to the method described for the preparation of compound Ik.
  • the title compound was collected as a white powder after purification.
  • the title compound (28 mg, 64%) was synthesized by coupling of the amine 7b (25 mg, 0.052 mmol) to 5-methanesulphonyl-methyl-amino)-N'-(l-phenyl-ethyl)-isophthalic acid according to the method described for the preparation of compound 11.
  • the title compound was collected as a white powder after lyophilization.
  • HATU (7.4 mg, 0.019 mmol) was added to a solution of the acid 1Od (7 mg, 0.019 mmol) and EtN 1 Pr 2 (10 ⁇ L, 0.06 mmol) in DMF (1 mL) and the resulting mixture was stirred for 2 min before adding 5-amino-6-benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid (1-benzylcarbamoyl- 2-methyl-propyl)-amide (9 mg, 0.019 mmol). The reaction mixture was stirred 5 min at r.t. and then concentrated under vacuum.
  • the title compound was prepared in 9% yield by coupling of the acid 1 Ie to 5-Amino-6- benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid (1 -benzylcarbamoyl-2-methyl-propyl)-amide according to the procedure described in Example 10 step e.
  • the title compound was prepared in 55% yield by coupling of the acid 12b to 5-amino-6- benzyloxy-4-hydroxy-2-isopropyl-hexanoic acid (1 -benzylcarbamoyl-2-methyl-propyl)-amide according to the procedure described in Example 10, step e.
  • the Grignard reagent phenylethylmagnesium chloride (1.0 M in THF, 0.32 mL, 0.32 mmol) was added dropwise to a cooled solution (-78 0 C) of the aldehyde 3-formyl-5- [methanesulphonyl(methyl)amino]benzoic acid methyl ester (0.26 mmol as 3.0 mL solution in 2/1 THF-Et 2 O), prepared as described in Bioorg. Med. Chem. letters, (2006), 641-644, and the mixture was stirred for 6 h. Saturated aqueous NH 4 Cl solution (5 mL) was added, the mixture was warmed to RT, and then more NH4CI solution (5 mL) was added.
  • HATU (16 mg, 0.042 mmol, 1.1 eq) was added, followed by DMF (0.50 mL) and then DIEA (20 ⁇ L, 0.0115 mmol, 3eq). After 2.5 h, the mixture was evaporated and then partitioned between 10% NaHCO 3 and CH 2 Cl 2 . The organic phase was washed with saturated aqueous NaCl, dried (Na 2 SO 4 ), and evaporated. Purification by prep HPLC-MS (gradient 30-65% MeCN - water, 0.1% TFA, in 4 min) gave the title compound as white solids (14.6 mg, 43% yield).
  • the methyl ester 19a (62.5 mg, 0.16 mmol) was hydro lyzed with 2N NaOH ( 0.25 niL, 0.5 mmol) in 2 mL 1/1 THF - MeOH by stirring at RT for 3h 15 min. The mixture was evaporated, diluted with 5 mL water, acidified with IN HCl , and extracted with EtOAc (3 x 10 mL). The organic phase was washed with saturated NaCl (10 mL), dried (Na 2 SO 4 ), and evaporated to give the carboxylic acid as white solids (56.4 mg, 93%).
  • Example 19 The procedure described in Example 19 was followed using the Grignard reagent [(S)-2-phenyl- 1-propylmagnesium bromide (prepared from (S)-l-bromo-2-phenylpropane)] instead of and the same starting aldehyde.
  • Grignard reagent [(S)-2-phenyl- 1-propylmagnesium bromide (prepared from (S)-l-bromo-2-phenylpropane)] instead of and the same starting aldehyde.
  • HATU coupling step Upon addition of water in the HATU coupling step a white precipitate was formed which was subsequently filtered, washed with water, and freeze-dried from MeCN/water to give the title compound as white solids.
  • the methyl ester of alcohol 19a' (80 mg, 0.29 mmol) was hydro lyzed by stirring with 0.45 rnL 2N NaOH (0.9 mmol) in 3 rnL 1/1 THF - MeOH for 3 h.
  • the mixture was diluted with water (10 mL), acidified, and then extracted with EtOAc (4 x 15 mL).
  • the organic phase was washed with saturated aqueous NaCl (10 mL), dried (Na 2 SO 4 ), and evaporated to give the carboxylic acid as white solids in quantitative yield. Half of this material was used in the next step.
  • FRET Fluorescence Resonance Energy Transfer
  • EDANS aminoethylaminonaphtalene sulphonate
  • Dabcyl 4'-dimethylaminoazobenzene
  • Arg-Glu(ED ANS)-Ile-His-Pro- Phe-His-Leu-Val-Ile-His-Thr-Lys(DABCYL)-Arg Sigma- Aldrich.
  • the cleavage site by human renin is the peptide bond between Leu and VaI. The compounds were tested at a range of concentrations whereas the enzyme and substrate concentrations were fixed.
  • the substrate was prepared at a 20 ⁇ M stock solution in DMSO.
  • To each well of a 96-well polypropylene plate was added the enzyme containing assay buffer (90.0 ⁇ l) and inhibitor of different concentrations (1 ⁇ l). To control wells were added DMSO (1 ⁇ l) instead of inhibitor.
  • the renin enzyme was preactivated by incubation at 37 0 C for 20 min whereafter the reactions were started by addition of substrate, 10 ⁇ l/well, thus giving a total volume of 100 ⁇ l/well and a substrate concentration of 2 ⁇ M.
  • the assay was performed during 20 min at 37 0 C.
  • the total concentration of DMSO was not above 1 %.
  • Product fluorescence emission filter 340 nM, excitation filter 500 nM
  • the Ki was determined by Prism Software.
  • Activity of the inhibitors was determined by measuring the fluorescence at ⁇ e X 340nm and ⁇ em 500nm.
  • Percent inhibition is calculated as follows: % Inhibition is equal to the (Fluorescence ⁇ inhibitor - Fluovescence ba ckground); divided by the (Fluorescence mmus inhibitor - Fluorescence ⁇ C £ g ro»«rf);
  • Table 1 shows enzymatic inhibition of renin for a representative selection of compounds according to the invention when tested in an renin enzyme assay such as the one described above.
  • Category A indicates ⁇ 50 nM inhibition
  • category B indicates 51 - 200 nM inhibition
  • category C indicates > 200 nM:
  • TruPointTM Beta-Secretase Assay Kit may be used.
  • the assay is based on the close proximity of two labels, a fluorescent europium chelate and a quencher of europium fluorescence. Fluorescence is strongly quenched when the labels are in close proximity of each other, and when the labels are separated, lanthanide fluorescence can be measured by time-resolved fluorometry (TRF).
  • TRF time-resolved fluorometry
  • the enzyme used in the assay is recombinant BACEl (produced in house) and the substrate is a 10 amino acids long peptide with a fluorescent europium chelate coupled to one end and a quencher of europium fluorescence (QSY 7) coupled via lysine to the other end; EU- CEVNLDAEFK-QSY 7.
  • the cleavage site by BACEl is the peptide bond between L and D.
  • a spectroscopic response is generated by peptidase cleavage, and the activity was measured by a continuous detection of increased fluorescence intensity exhibited by the cleavage product.
  • the compounds were tested at a range of concentrations whereas the enzyme and substrate concentrations were fixed.
  • the substrate was prepared at a 120 ⁇ M stock solution in distilled water. The stock solution was diluted to 400 nM in an amount which was needed for the day.
  • To each well of a 96-well half area polystyrene plate was added the enzyme containing reaction buffer (15 ⁇ l) and inhibitor of different concentrations in DMSO (1 ⁇ l). To control wells were added reaction buffer (15 ⁇ l) and DMSO (1 ⁇ l).
  • the enzyme with inhibitor in DMSO was preincubated at room temperature (20-25 0 C) for 30 min whereafter the reactions were started by addition of substrate, 15 ⁇ l/well, thus giving a total volume of 31 ⁇ l/well and a substrate concentration of 200 nM.
  • Product TR- fluorescence was monitored during 90 min with a 1420 VICTOR and presented as Relative Fluorescence units (RFu).
  • the IC50 value was calculated with GraFit software.
  • Activity of the inhibitors was determined by measuring the TR- fluorescence at ⁇ e X 330 nm and ⁇ em 615 nm. The inhibition is calculated as follows:
  • Table 2 shows the enzymatic inhibition exhibited by a representative selection of compounds according to the invention when tested in a BACE enzyme assay such as the one described above.
  • Category A indicates an IC50 value of ⁇ 1 ⁇ M
  • category B indicates 1 - 5 ⁇ M
  • category C indicates > 5 ⁇ M.

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Abstract

L'invention concerne des composés de formule (I). Elle concerne des N-oxydes, des sels d'addition, des amines quaternaires, des complexes métalliques, des formes isomères stéréochimiques et des métabolites de ces composés. Dans la formule (I), W représente H, un alkyle en C1-C6, un cycloalkyle en C3-C6, un aryle ou un hétérocyclyle; Q représente un aryle ou un hétérocyclyle; A représente un noyau aromatique ou partiellement insaturé, à cinq ou six éléments saturés; D représente une formule (II) ou une formule (III); et les autres variables sont telles que définies dans la description. Les composés de l'invention sont des inhibiteurs d'aspartyl-protéases tels que de la rénine et de la BACE et sont, entre autres, utiles dans le traitement et/ou la prophylaxie de troubles associés à des activités du système rénine-angiotensine (RAS), tels que l'hypertension, l'insuffisance cardiaque et l'insuffisance rénale et dans le traitement et/ou la prophylaxie de troubles associés à l'activité de la BACE, notamment la maladie d'Alzheimer.
PCT/EP2008/053765 2007-03-30 2008-03-28 Dérivés d'amide utilisés en tant qu'inhibiteurs d'aspartyl-protéases Ceased WO2008119772A1 (fr)

Applications Claiming Priority (4)

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EP07105324.3 2007-03-30
EP07105325.0 2007-03-30
EP07105324 2007-03-30
EP07105325 2007-03-30

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WO2008119772A1 true WO2008119772A1 (fr) 2008-10-09

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012107153A1 (fr) 2011-02-08 2012-08-16 Merck Patent Gmbh Dérivés d'aminostatine pour le traitement de l'arthrose
WO2014015934A1 (fr) 2012-07-24 2014-01-30 Merck Patent Gmbh Dérivés d'hydroxystatine pour le traitement de l'arthrose
WO2014127881A1 (fr) 2013-02-25 2014-08-28 Merck Patent Gmbh Dérivés de 2-amino-3,4-dihydroquinazoline et leur utilisation comme inhibiteurs de la cathepsine d
WO2015018472A1 (fr) 2013-08-06 2015-02-12 Merck Patent Gmbh Application intra-articulaire de pepstatine dans l'arthrose

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
J. RAHUEL, ET AL.: "Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin", CHEMISTRY AND BIOLOGY, vol. 7, no. 7, 16 June 2000 (2000-06-16), CURRENT BIOLOGY, LONDON, GB, pages 493 - 504, XP002254255, ISSN: 1074-5521 *
N.E. MEALY, ET AL.: "Aliskiren fumarate", DRUGS OF THE FUTURE, vol. 26, no. 12, December 2001 (2001-12-01), BARCELONA, ES, pages 1139 - 1148, XP009017211, ISSN: 0377-8282 *
P. BÜHLMAYER, ET AL.: "Synthesis and biological activity of some transition-state inhibitors of human renin", JOURNAL OF MEDICINAL CHEMISTRY, vol. 31, no. 9, September 1988 (1988-09-01), AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US, pages 1839 - 1846, XP002463996, ISSN: 0022-2623 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012107153A1 (fr) 2011-02-08 2012-08-16 Merck Patent Gmbh Dérivés d'aminostatine pour le traitement de l'arthrose
WO2014015934A1 (fr) 2012-07-24 2014-01-30 Merck Patent Gmbh Dérivés d'hydroxystatine pour le traitement de l'arthrose
WO2014127881A1 (fr) 2013-02-25 2014-08-28 Merck Patent Gmbh Dérivés de 2-amino-3,4-dihydroquinazoline et leur utilisation comme inhibiteurs de la cathepsine d
WO2015018472A1 (fr) 2013-08-06 2015-02-12 Merck Patent Gmbh Application intra-articulaire de pepstatine dans l'arthrose

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